POLYPROPYLENE CONTAINERS FOR PROSTAGLANDIN PRODUCTS

Description

[0001] This invention relates to aqueous prostaglandin compositions packaged in polypropylene containers.

BACKGROUND OF THE INVENTION

[0002] As used herein, "LDPE" means low density polyethylene.

[0003] Prostaglandins have notoriously low water solubility, and are generally unstable. Attempts have been made to solubilize and stabilize various prostaglandins by complexing them with different cyclodextrins. See, for example: EP 330 511 A2 (Ueno et al.) and EP 435 682 A2 (Wheeler). These attempts have met with varying success.

[0004] Surfactants and/or solubilizers have been used with other types of drugs having low water solubility. However, the addition of surfactants and/or solubilizers may enhance or adversely affect the chemical stability of drug compounds. See Surfactant Systems, Their Chemistry, Pharmacy, and Biology, (eds. Attwood et al.), Chapman and Hall, New York, 1983, Ch. 11, particularly pp. 698 - 714.

[0005] The use of non-ionic surfactants, such as polyethoxylated castor oils, as solubilizing agents is known. See, for example, US 4,960,799 (Nagy).

[0006] The use of non-ionic surfactants such as polyethoxylated castor oils in stable emulsions is also known. US 4,075,333 (Josse) discloses stable, intravenous emulsion formulations of vitamins. El-Sayed et al., Int. J. Pharm., 13:303-12 (1983) discloses stable oil-in-water emulsions of an antineoplastic drug. US 5,185,372 (Ushio et al.) discloses topically administrable ophthalmic formulations of vitamin A which are stable preparations in which a non-ionic surfactant is used to form an emulsion of vitamin A in an aqueous medium.

[0007] U.S. Patent No. 5,631,287 (Schneider) discloses storage-stable prostaglandin compositions containing a chemically stabilizing amount of a polyethoxylated castor oil.

[0008] Presently, there are only two commercially available ophthalmic multi-dose prostaglandin products, Xalatan™ (latanoprost solution; Upjohn) and Rescula™ (isopropyl unoprostone; Fujisawa). Xalatan™ is packed in a polyethylene (LDPE) container. According to the package insert, this product must be stored under refrigeration at 2 - 8° C until opened. Once opened, the container may be stored at room temperature up to 25° C for six weeks. Rescula™ is also packaged in a polyethylene (LDPE) container.

SUMMARY OF THE INVENTION

[0009] The present invention is directed to pharmaceutical products containing an aqueous prostaglandin composition packaged in polypropylene containers. Aqueous prostaglandin compositions packaged polypropylene containers are more stable than those packaged in polyethylene containers.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] 

Figure 1 compares the stability of Formulation D in clear glass, low density polyethylene and isotactic polypropylene bottles at 65 °C.

Figure 2 compares the stability of Formulation E in clear glass, low density polyethylene and isotactic polypropylene bottles at 65 °C.

Figure 3 compares the stability of Formulation F in clear glass, low density polyethylene and isotactic polypropylene bottles at 65 °C.

Figure 4 compares the stability of Formulation G in clear glass, low density polyethylene and isotactic polypropylene bottles at 65 °C.

DETAILED DESCRIPTION

[0011] As used herein, "aqueous prostaglandin compositions" means aqueous compositions containing at least one prostaglandin and a major amount of water, wherein water makes up the continuous phase of the composition.

[0012] As used herein, "polypropylene" means polypropylene, substantially free (e.g., less than about 5 wt.%) of non-polypropylene olefins. The term polypropylene includes, for example, isotactic polypropylene, syndiotactic polypropylene and blends of isotactic and syndiotactic polypropylene.

[0013] The terms "prostaglandin" and "PG" are generally used to describe a class of compounds which are analogues and derivatives of prostanoic acid (1). PG's may be further classified, for example, according to their 5-membered ring structure, using a letter designation; PG's of A-J series are known. PG's may be further classified based on the number of unsaturated bonds on the side chain, e.g., PG₁'s (13,14-unsaturated), PG₂'s (13,14- and 5,6-unsaturated), and PG₃'s (13,14-,5,6- and 17,18-unsaturated). See U.S. Patent No. 5,631,287.

[0014] The prostaglandins which may be utilized in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogues, and their pharmaceutically acceptable esters and salts. Such prostaglandins include the natural compounds: PGE₁, PGE₂, PGE₃, PGF_1α, PGF_2α, PGF_3α, PGD₂ and PGI₂ (prostacyclin), as well as analogues and derivatives of these compounds which have similar biological activities of either greater or lesser potencies. Analogues of the natural prostaglandins include but are not limited to: alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer enhanced or sustained potency by reducing biological metabolism or alter selectivity of action; saturation (e.g., 13,14-dihydro) or unsaturation (e.g., 2,3-didehydro, 13,14-didehydro), which confer sustained potency by reducing biological metabolism or alter selectivity of action; deletions or replacements (e.g., 11-deoxy, 9-deoxo-9-methylene), chloro (or halogen) for oxygen (e.g., 9β-chloro), oxygen for carbon (e.g., 3-oxa), lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxygen (e.g., 1-CH₂OH,1-CH₂OAcyl) which enhance chemical stability and/or selectivity of action; and ω-chain modifications (e.g., 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which enhance selectivity of action and reduce biological metabolism. Derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which may be attached to the 1-carboxyl group or any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It should be understood that the terms "analogues" and "derivatives" include compounds that exhibit functional and physical responses similar to those of prostaglandins per se.

[0015] Specific examples of prostaglandins suitable for use in the products of the present invention include the following compounds:

Compound No.

[0016] 

1. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;

2. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

3. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;

4. (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

5. (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

6. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide;

7. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide;

8. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester;

9. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;

10. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl ester;

11. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester;

12. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester;

13. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester;

14. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;

15. (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid isopropyl ester;

16. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;

17. (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

18. (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

19. (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester;

20. (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester;

21. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diof;

22, (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;

23. (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19.,20-pentanor-13-prostynoic acid;

24. Latanoprost (PhXA41);

25. Cloprostenol isopropyl ester;

26. (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid;

27. (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-ch4orophenyf)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid;

28. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

29. (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

30. (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide;

31. PGF_2α isopropyl ester; and

32. Fluprostenol isopropyl ester.

[0017] All of the foregoing compounds are known. Preferred prostaglandins for use in the compositions of the present invention are Compounds 2 and 32 above.

[0018] The prostaglandin compositions packaged in polypropylene containers according to the present invention can be adapted for any route of administration. Compositions adapted for topical administration to the ears, nose or eyes are preferred, with compositions prepared for topical administration to the eye being most preferred.

[0019] In addition to one or more prostaglandins, the aqueous compositions of the present invention also contain at least one surfactant in order to help solubilize or disperse the prostaglandin in the composition. Surfactants also inhibit or prevent the adsorption of the prostaglandin on to the container walls. The surfactant may be any pharmaceutically acceptable surfactant, such as pharmaceutically acceptable cationic, anionic or nonionic surfactants. Examples of suitable surfactants include polyethoxylated castor oils, such as those classified as PEG-2 to PEG-200 castor oils, as well as those classified as PEG-5 to PEG-200 hydrogenated castor oils. Such polyethoxylated castor oils include those manufactured by Rhone-Poulenc (Cranbury, New Jersey) under the Alkamuls® brand, those manufactured by BASF (Parsippany, New Jersey) under the Cremophor® brand, and those manufactured by Nikko Chemical Co., Ltd. (Tokyo, Japan) under the Nikkol brand. Preferred polyethoxylated castor oils are those classified as PEG-15 to PEG-50 castor oils, and more preferred are PEG-30 to PEG-35 castor oils. It is most preferred to use those polyethoxylated castor oils known as Cremophor® EL and Alkamuls® EL-620. Preferred polyethoxylated hydrogenated castor oils are those classified as PEG-25 to PEG-55 hydrogenated castor oils. The most preferred polyethoxylated hydrogenated castor oil is PEG-40 hydrogenated castor oil, such as Nikkol HCO-40.

[0020] The aqueous compositions of the present invention optionally comprise other formulatory ingredients, such as antimicrobial preservatives, tonicity agents, and buffers. Many such formulatory ingredients are known. Examples of suitable antimicrobial preservatives for multi-dose topically administrable ophthalmic formulations include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Polyquad® and other agents equally well known to those skilled in the art. Such preservatives, if present, will typically be employed in an amount between about 0.001 and about 1.0 wt.%. Examples of suitable agents that may be utilized to adjust the tonicity or osmolality of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. Such agents, if present, will be employed in an amount between about 0.1 and about 10.0 wt.%. Examples of suitable buffering agents include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutically acceptable salts of the foregoing, and tromethamine. Such buffers, if present, will be employed in an amount between about 0.001 and about 1.0 wt.%.

[0021] The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers and gelling polysaccharides, such as those described in US 4,861,760 (Mazuel et al), US 4,911,920 (Jani et al.), and in commonly assigned US Serial No. 08/108,824 (Lang et al.).

[0022] As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for delivery of aqueous compositions. In the preferred case of topical ophthalmic delivery, the compositions may be formulated as solutions, suspensions or emulsions, for example. Topically administrable ophthalmic compositions have a pH between 3.5 to 8.0 and an osmolality between 260 to 320 milliOsmoles per kilogram (mOsm/kg).

[0023] The preferred topically administrable aqueous compositions are preferably packaged in a "small volume" bottle. As used herein, the term "small volume" bottle shall mean a bottle of a size sufficient to hold a quantity of liquid medicine sufficient for 1 - 3 topical doses per day over 1 - 2 months, generally about 20 mL or less. For example, small volume containers include 5 mL-, 10 mL- and 15 mL-sized bottles adapted for topically administering eye drops. Small volume bottles made from syndiotactic polypropylene are easier to squeeze than those made from isotactic polypropylene, and oval bottles are easier to squeeze than round bottles. Accordingly, the aqueous compositions adapted for topical ophthalmic administration are preferably packaged in oval, syndiotactic polypropylene bottles.

[0024] The invention will be further illustrated by the following examples.

Preparation of Formulations A - G:

[0025] Formulations A - G shown in Examples 1 - 7 below were prepared as follows. To a clean glass vessel of appropriate size was added approximately 75% of the batch volume of water. To this was sequentially added sodium acetate or tromethamine and boric acid, followed by mannitol, EDTA, benzalkonium chloride and either Cremophor® EL or HCO-40 so that there was complete dissolution of one ingredient prior to the addition of the next ingredient. Next the pH of the solution was adjusted using NaOH and/or HCl, and the water was added to bring the volume to 100%.

[0026] In a separate clean glass vessel, the appropriate quantity of prostaglandin was added, followed by the appropriate quantity of the vehicle whose preparation was described above. The vessel was then tightly capped and sonicated in an ultrasonic bath for one hour or alternatively stirred with a magnetic stir bar overnight, until the prostaglandin was completely dissolved. The resulting solution was then sterile filtered (0.2 µm filter).

EXAMPLE 1

[0027] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%) A
Compound No. 32	0.001 + 5%
(prostaglandin)	excess
Cremophor® EL	0.5
Tromethamine	0.12
Boric Acid	0.3
Mannitol	4.6
Disodium EDTA	0.01
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCI	q.s. to pH 7.4
Purified Water	q.s. to 100%

In order to test the compatibility of Formulation A with packaging materials, the following procedure was used. ETO-sterilized clear LDPE, gamma-sterilized clear LOPE, gamma-sterilized opaque LDPE and ETO-sterilized isotactic polypropylene bottles were cut into thin rectangular pieces (2 mm x 10 mm). The isotactic polypropylene bottles were made from Rexene™ isotactic polypropylene (Huntsman Chemical, Inc., Odessa, TX). Approximately 0.5 g of each bottle material was transferred into separate 10-mL clear glass ampules (this amount roughly corresponds to the surface area with which a 5- mL-sized product would interact). Each glass ampule was then filled with 5 mL of Formulation A and sealed. The packaging materials were tested in this way in order to eliminate evaporation effects. The sealed ampules were stored in an oven at 55°C and were pulled out at the indicated times for HPLC analysis. The stability of the prostaglandin in Formulations A was evaluated using a semi-gradient HPLC method, employing a Delta-Pak™ C-18 column (150 x 4.6 mm), 5 µm, 100Å connected with a Delta-Pak™ C-18 precolumn. The reference standard solution contained the prostaglandin in a water/ methanol (70:30) solution.

Mobile Phase A:

1-Octanesulfonic Acid Sodium Salt (100mM); pH=3.7

Mobile Phase B:

Acetonitrile / Methanol (10:1)

Injection Volume:

100µL

Detector:

220 nm

Column Temperature:

25°C

Semi-Gradient Flow Rate:

1.6 mL/min

Run Time (minutes)	Mobile Phase A Flow Rate (mL/min)	Mobile Phase B Flow Rate (mL/min)
0	0.94	0.66
1	0.94	0.66
35	0.94	0.66
40	0.16	1.44
45	0.94	0.66
50	0.94	0.66

[0028] The results of the compatibility tests are shown below in Table 1.

TABLE 1

COMPATIBILITY OF FORMULATION A
TIME-POINT (weeks)	PERCENT DRUG REMAINING (55°C)
	CLEAR GLASS AMPULES (NON- STERILIZED)	CLEAR LDPE BOTTLE (ETO STERILIZED)	CLEAR LDPE BOTTLE (GAMMA STERILIZED)	OPAQUE-LDPE BOTTLE (GAMMA STERILIZED)	ISOTACTIC POLYPROPYLENE (ETO STERIUZED)
INITIAL	100.0	100.0	100.0	100.0	100.0
2	99.5	96.1	91.4	92.0	102.2
4	94.6	93.5	86.6	88.6	100.0
8	96.3	93.2	80.6	82.8	101.0
% Change (8 Weeks - Initial)	(-)2.7%	(-)6.8%	(-)19.4%	(-)17.2%	(+)1.0%

EXAMPLE 2

[0029] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%) B
Compound No. 32 (prostaglandin)	0.001 + 5% excess
Cremophor® EL	0.1
Tromethamine	0.12
Boric Acid	0.3
Mannitol	4.6
Disodium EDTA	0.01
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCI	q.s. to pH 7.4
Purified Water	q.s. to 100%

[0030] The compatibility of Formulation B with glass, LDPE and polypropylene containers was determined by monitoring the stability of the drug in the manner described above in Example 1 for Formulation A. The results are shown below in Table 2.

TABLE 2

COMPATIBILITY OF FORMULATION B
TIME- POINT (weeks)	PERCENT DRUG REMAINING (55°C)
	CLEAR GLASS AMPULES (NON. STERILIZED)	CLEAR-LDPE BOTTLE (ETO STERILIZED)	CLEAR-LDPE BOTTLE (GAMMA STERILIZED)	OPAQUE-LDPE BOTTLE (GAMMA STERILIZED)	ISOTACTIC POLYPROPYLENE (ETO STERILlZED)
INITIAL	100.0	100.0	100.0	100.0	100.0
2	97.2	96.2	89.4	88.4	96.3
4	96.5	94.5	84.6	82.9	97.3
8	96.8	92.7	79.2	77.9	97.0
% Change (8 Weeks - Initial)	(-)3.2%	(-)7.3%	(-)20.8%	(-)22.1%	(-)3.0%

EXAMPLE 3

[0031] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%)
	C
Compound No. 32 (prostaglandin)	0.003
HC0-40	0.5
Tromethamine	0.12
Boric Acid	0.3
Mannitol	4.6
Disodium EDTA	0.01
Benzalkonium Chloride	0.015
NaOH and/or HCI	q.s. to pH 6.0
Purified Water	q.s. to 100%

[0032] The compatibility of Formulation C in non-sterilized syndiotactic polypropylene bottles, ETO-sterilized syndiotactic polypropylene bottles and isotactic polypropylene (Rexene®) bottles was determined as follows. The bottles were filled with 5 mL of sterile Formulation C, then stored in an oven at 55 °C and pulled at the indicated time points for HPLC analysis as described above. The syndiotactic polypropylene bottles were made from FINA 3721 WZ syndiotactic polypropylene (FINA Oil and Chemical Co., Dallas, TX.). The compatibility results are shown below in Tables 3 and 4. Table 3 compares the compatibility of Formulation C in non-sterilized vs. ETO-sterilized syndiotactic polypropylene bottles. Table 4 compares the compatibility of Formulation C in non-sterilized isotactic and syndiotactic polypropylene bottles.

TABLE 3

COMPATIBILITY OF FORMULATION C IN STERILIZED VS. NON-STERILIZED POLYPROPYLENE BOTTLES
TIME-POINT (weeks)	PERCENT DRUG REMAINING (55°C)
	SYNDIOTACTIC POLYPROPYLENE BOTTLES (NON-STERILIZED)	SYNDIOTACTIC POLYPROPYLENE BOTTLES (ETO-STERILIZED)
INITIAL	100.0	100.0
2	98.6	99.5
4	97.8	98.7
% Change (4 Weeks -Initial)	(-)2.2%	(-)1.3%

TABLE 4

COMPATIBILITY OF FORMULATION C IN ISOTACTIC VS. SYNDIOTACTIC POLYPROPYLENE BOTTLES
TIME-POINT (weeks)	PERCENT DRUG REMAINING (55°C)
	ISOTACTIC POLYPROPYLENE BOTTLES (NON-STERILIZED)	SYNDIOTACTIC POLYPROPYLENE BOTTLES (NON-STERILlZED)
INITIAL	100.0	100.0
2	100.5	98.4
4	99.8	96.4
8	98.0	97.2
% Change (8 Weeks - Initial)	(-) 2.0%	(-) 2.8%

EXAMPLE 4

[0033] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%)
	D
Compound No. 2 (prostaglandin)	0.012+5% excess
Cremophor® EL	0.5
Sodium Acetate (trihydrate)	0.07
Mannitol	4.3
Disodium EDTA	0.1
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCl	q.s. to pH 5.0
Purified Water	q.s. to 100%

[0034] The stability of the prostaglandin in Formulation D was evaluated in clear glass, ETO-sterilized LOPE, and ETO-sterilized isotactic polypropylene bottles as follows.

[0035] The bottles were filled with sterile Formulation D and stored in an oven at 65 °C, then pulled at the indicated times for HPLC analysis. In this case, the HPLC data was generated using a Phenomenex 150 X 4.6 mm HPLC column with Spherisorb® 10 ODS(2) packing. The mobile phase was 560 mL phosphate to 440 mL acetonitrile, adjusted to a pH of about 8.5. The flow rate was 1 mL/minute, the detection was 200 nm UV, and the injection quantity was 20 mcL. The compatibility results are shown in Figure 1

EXAMPLE 5

[0036] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%) E
Compound No. 2 (prostaglandin)	0.012 + 5% excess
Cremophor® EL	1.5
Sodium Acetate	0.07
(trihydrate)
Mannitol	4.3
Disodium EDTA	0.1
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCI	q.s. to pH 5.0
Purified Water	q.s. to 100%

[0037] The stability of the prostaglandin in Formulation E was evaluated in clear glass, LDPE, and isotactic polypropylene bottles at 65 °C according to the procedure described in Example 4 for Formulation D. The results are shown in Figure 2.

EXAMPLE 6

[0038] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%) F
Compound No. 2 (prostaglandin)	0.012 + 5% excess
Cremophor® EL	2.0
Sodium Acetate	0.07
(trihydrate)
Mannitol	4.3
Disodium EDTA	0.1
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCI	q.s. to pH 5.0
Purified Water	q.s. to 100%

[0039] The stability of the prostaglandin in Formulation F was evaluated in dear glass, LOPE, and isotactic polypropylene bottles at 65 °C according to the procedure described in Example 4 for Formulation D. The results are shown in Figure 3.

EXAMPLE 7

[0040] The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT	FORMULATION (w/v%) G
Compound No. 2 (prostaglandin)	0.012 + 5% excess
Cremophor® EL	1.0
Sodium Acetate	0.07
(trihydrate)
Mannitol	4.3
Disodium EDTA	0.1
Benzalkonium Chloride	0.01 + 5% excess
NaOH and/or HCl	q.s. to pH 5.0
Purified Water	q.s. to 100%

[0041] The stability of the prostaglandin in Formulation G was evaluated in clear glass, LDPE, and isotactic polypropylene bottles at 65 °C according to the procedure described in Example 4 for Formulation D. The results are shown in Figure 4.

Claims

1. Use of a polypropylene container for increasing the stability of an aqueous prostaglandin composition which is packaged within the container and which comprises a prostaglandin and a pharmaceutically acceptable surfactant.

2. The use of claim 1 wherein the aqueous prostaglandin composition comprises a prostaglandin selected from the group consisting of
   (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-18,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19, 20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;
   (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9R, 11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester,
   (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester,
   (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester;
   (5Z)-(9S,11R, 15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclahexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diol;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;
   (9R, 11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoic acid;
   latanoprost (PhXA41);
   cloprostenol isopropyl ester;
   (5Z)-(9S,11R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid;
   (5Z)-(9S,11 R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide;
   PGF₂α isopropyl ester; and
   fluprostenol isopropyl ester.

3. The use of claim 2 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; and fluprostenol isopropyl ester.

4. The use of claim 1 wherein the composition is adapted for topical ophthalmic administration and the surfactant comprises a polyethoxylated castor oil.

5. The use of claim 4 wherein the polyethoxylated castor oil is selected from the group consisting of PEG-2 to PEG-200 castor oils; and PEG-5 to PEG-200 hydrogenated castor oils.

6. The use of claim 1 wherein the polypropylene container is a polypropylene bottle adapted for topical delivery and wherein the polypropylene is selected from the group consisting of isotactic polypropylene, syndiotactic polypropylene and blends of isotactic and syndiotactic polypropylene.

7. The use of claim 1 wherein the aqueous prostaglandin composition is adapted for topical ophthalmic administration and the polypropylene container is a small volume bottle adapted for topical ophthalmic delivery.

8. The use of claim 7 wherein the polypropylene container is an oval, syndiotactic polypropylene bottle.

9. The use of claim 8 wherein the aqueous prostaglandin composition is a multi-dose composition comprising an ophthalmically acceptable preservative.

10. A method of increasing the stability of an aqueous prostaglandin composition comprising a prostaglandin and a pharmaceutically acceptable surfactant wherein the method comprises:

packaging the aqueous prostaglandin composition in a polypropylene container.

11. The method of claim 10 wherein the aqueous prostaglandin composition comprises a prostaglandin selected from the group consisting of
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester,
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;
   (5Z,13E)-(9S,11R, 15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid isopropyl ester;
   (5Z)-(9R,11R, 15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester;
   (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diol;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;
   (9R, 11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoic acid;
   latanoprost (PhXA41);
   cloprostenol isopropyl ester;
   (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid;
   (5Z)-(9S,11R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9S,11 R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide;
   PGF₂α isopropyl ester; and
   fluprostenol isopropyl ester.

12. The method of claim 11 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18, 19,20-pentanor-5-prostenoic acid isopropyl ester; and fluprostenol isopropyl ester.

13. The method of claim 10 wherein the composition is adapted for topical ophthalmic administration and the surfactant comprises a polyethoxylated castor oil.

14. The method of claim 13 wherein the polyethoxylated castor oil is selected from the group consisting of PEG-2 to PEG-200 castor oils; and PEG-5 to PEG-200 hydrogenated castor oils.

15. The method of claim 10 wherein the polypropylene container is a polypropylene bottle adapted for topical delivery and wherein the polypropylene is selected from the group consisting of isotactic polypropylene, syndiotactic polypropylene and blends of isotactic and syndiotactic polypropylene.

16. The method of claim 10 wherein the aqueous prostaglandin composition is adapted for topical ophthalmic administration and the polypropylene container is a small volume bottle adapted for topical ophthalmic delivery.

17. The method of claim 16 wherein the polypropylene container is an oval, syndiotactic polypropylene bottle.

18. The method of claim 17 wherein the aqueous prostaglandin composition is a multi-dose composition comprising an ophthalmically acceptable preservative.

19. A prostaglandin product comprising:

a) an aqueous prostaglandin composition comprising a therapeutically effective amount of at least one prostaglandin and a pharmaceutically acceptable surfactant; and

b) a polypropylene container; wherein the aqueous prostaglandin composition is packaged in the polypropylene container.

20. The prostaglandin product of claim 19 wherein the prostaglandin is selected from the group consisting of
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9S,11R,15R)-15-cycfohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide;
   (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;
   (5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18;19,20-tetranor-5,13-prostadienoic acid isopropyl ester;
   (5Z)-(9R,11 R, 15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;
   (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester;
   (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diol;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18, 9 9,20-pentanor-5-prostenol;
   (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoic acid;
   latanoprost (PhXA41);
   cloprostenol isopropyl ester;
   (5Z)-(9S,11R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid;
   (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid;
   (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;
   (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide;
   PGF₂α isopropyl ester; and
   fluprostenol isopropyl ester.

21. The prostaglandin product of claim 20 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; and fluprostenol isopropyl ester.

22. The prostaglandin product of claim 19 wherein the composition is adapted for topical ophthalmic administration and the surfactant comprises a polyethoxylated castor oil.

23. The prostaglandin product of claim 22 wherein the polyethoxylated castor oil is selected from the group consisting of PEG-2 to PEG-200 castor oils; and PEG-5 to PEG-200 hydrogenated castor oils.

24. The prostaglandin product of claim 19 wherein the polypropylene container is a polypropylene bottle adapted for topical delivery and wherein the polypropylene is selected from the group consisting of isotactic polypropylene, syndiotactic polypropylene and blends of isotactic and syndiotactic polypropylene.

25. The prostaglandin product of claim 19 wherein the aqueous prostaglandin composition is adapted for topical ophthalmic administration and the polypropylene container is a small volume bottle adapted for topical ophthalmic delivery.

26. The prostaglandin product of claim 25 wherein the polypropylene container is an oval, syndiotactic polypropylene bottle.

27. The prostaglandin product of claim 26 wherein the aqueous prostaglandin composition is a multi-dose composition comprising an ophthalmically acceptable preservative.

Ansprüche

1. Verwendung eines Polypropylenbehälters zur Erhöhung der Stabilität einer wässerigen Prostaglandinzusammensetzung, die in dem Behälter verpackt ist und die ein Prostaglandin und ein pharmazeutisch akzeptables oberflächenaktives Mittel umfaßt.

2. Verwendung nach Anspruch 1, wobei die wässerige Prostaglandinzusammensetzung ein Prostaglandin umfaßt, das aus der Gruppe, bestehend aus
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;
(5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureamid;
(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-N,N-dimethylamid;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclohexylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclopentylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäurecyclopentylester;
(5Z)-(9R,11R,15R)-9-Chlor-13-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,2-dimethylpropylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureadamantylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-diisopropylphenylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-dimethylphenylester;
(5Z,13E)-(9S,11R, 15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureisopropylester;
(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;
(5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5E)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z)-(9R,11R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostensäuretertbutylester;
(5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostensäureisopropylester;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prosten-11,15-diol;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15 dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;
(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinsäure;
Latanoprost (PhXA41);
Cloprostenolisopropylester;
(5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5-prostensäure;
(5Z)-(9S,11R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5,13-prostadiensäure;
(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z)-(9S,11R,15S)-15-Cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;
(5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureamid;
PGF_2α-Isopropylester und
Fluprostenolisopropylester ausgewählt ist.

3. Verwendung nach Anspruch 2, wobei das Prostaglandin aus der Gruppe, bestehend aus (5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester und Fluprostenolisopropylester ausgewählt ist.

4. Verwendung nach Anspruch 1, wobei die Zusammensetzung auf die topische ophthalmische Verabreichung abgestimmt ist, und das oberflächenaktive Mittel ein polyethoxyliertes Rizinusöl umfaßt.

5. Verwendung nach Anspruch 4, wobei das polyethoxylierte Rizinusöl aus der Gruppe, bestehend aus PEG-2- bis PEG-200-Rizinusölen und hydrierten PEG-5- bis PEG-200-Rizinusölen ausgewählt ist.

6. Verwendung nach Anspruch 1, wobei der Polypropylenbehälter eine Polypropylenflasche ist, die auf topische Abgabe abgestimmt ist, und wobei das Polypropylen aus der Gruppe, bestehend aus isotaktischem Polypropylen, syndiotaktischem Polypropylen and Gemischen aus isotaktischem und syndiotaktischem Polypropylen ausgewählt ist.

7. Verwendung nach Anspruch 1, wobei die wässerige Prostaglandinzusammensetzung auf topische ophthalmische Verabreichung abgestimmt ist und der Polypropylenbehälter eine Flasche mit einem kleinen Volumen ist, die auf topische ophthalmische Abgabe abgestimmt ist.

8. Verwendung nach Anspruch 7, wobei der Polypropylenbehälter eine ovale, syndiotaktische Polypropylenflasche ist.

9. Verwendung nach Anspruch 8, wobei die wässerige Prostaglandinzusammensetzung eine Mehrfachdosierungszusammensetzung ist, die ein ophthalmisch akzeptables Konservierungsmittel umfaßt.

10. Verfahren zur Erhöhung der Stabilität einer wässerigen Prostaglandinzusammensetzung, die ein Prostaglandin und ein pharmazeutisch akzeptables oberflächenaktives Mittel umfaßt, wobei das Verfahren:

die Verpackung der wässerigen Prostaglandinzusammensetzung in einem Polypropylenbehälter umfaßt.

11. Verfahren nach Anspruch 10, wobei die wässerige Prostaglandinzusammensetzung ein Prostaglandin umfaßt, das aus der Gruppe, bestehend aus:

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroacy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9S,11R, 15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-N,N-dimethylamid;

(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1 -methylcyclohexylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclopentylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäurecyclopentylester;

(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,2-dimethylpropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureadamantylester;

(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-diisopropylphenylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-dimethylphenylester;

(5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5E)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19, 20-pentanor-5-prostensäuretertbutylester;

(5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prosten-11,15-diol;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;

(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinsäure;

Latanoprost (PhXA41);

Cloprostenolisopropylester;

(5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5-prostensäure;

(5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19, 20-tetranor-5,13-prostadiensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9S,11R,15S)-15-Cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureamid;

PGF_2α-Isopropylester und

Fluprostenolisopropylester ausgewählt ist.

12. Verfahren nach Anspruch 11, wobei das Prostaglandin aus der Gruppe, bestehend aus (5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester und Fluprostenolisopropylester ausgewählt ist.

13. Verfahren nach Anspruch 10, wobei die Zusammensetzung auf die topische ophthalmische Verabreichung abgestimmt ist, und das oberflächenaktive Mittel ein polyethoxyliertes Rizinusöl umfaßt.

14. Verfahren nach Anspruch 13, wobei das polyethoxylierte Rizinusöl aus der Gruppe, bestehend aus PEG-2- bis PEG-200-Rizinusölen und hydrierten PEG-5- bis PEG-200-Rizinusölen ausgewählt ist.

15. Verfahren nach Anspruch 10, wobei der Polypropylenbehälter eine Polypropylenflasche ist, die auf topische Abgabe abgestimmt ist, und wobei das Polypropylen aus der Gruppe, bestehend aus isotaktischem Polypropylen, syndiotaktischem Polypropylen und Gemischen aus isotaktischem und syndiotaktischem Polypropylen ausgewählt ist.

16. Verfahren nach Anspruch 10, wobei die wässerige Prostaglandinzusammensetzung auf topische ophthalmische Verabreichung abgestimmt ist, und der Polypropylenbehälter eine Flasche mit einem kleinen Volumen ist, die auf topische ophthalmische Abgabe abgestimmt ist.

17. Verfahren nach Anspruch 16, wobei der Polypropylenbehälter eine ovale, syndiotaktische Polypropylenflasche ist.

18. Verfahren nach Anspruch 17, wobei die wässerige Prostaglandinzusammensetzung eine Mehrfachdosierungszusammensetzung ist, die ein ophthalmisch akzeptables Konservierungsmittel umfaßt.

19. Prostaglandinprodukt, umfassend:

a) eine wässerige Prostaglandinzusammensetzung, die eine therapeutisch wirksame Menge von zumindest einem Prostaglandin und ein pharmazeutisch akzeptables oberflächenaktives Mittel umfaßt; und

b) einen Polypropylenbehälter, wobei die wässerige Prostaglandinzusammensetzung in dem Polypropylenbehälter verpackt ist.

20. Prostaglandinprodukt nach Anspruch 19, wobei das Prostaglandin aus der Gruppe, bestehend aus:

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor 5-prostensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-N,N-dimethylamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclohexylester;

(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclopentylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäurecyclopentylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,2-dimethylpropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureadamantylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-diisopropylphenylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-dimethylphenylester;

(5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureisopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5E)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9R,11R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostensäuretertbutylester;

(5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostensäureisopropylester;

(5Z)-(9R,11R, 15R)-9-Chlor-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prosten-11,15-diol;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15 dihydroxy-3-oxa-16,17,18,19, 20-pentanor-5-prostenol;

(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinsäure;

Latanoprost (PhXA41);

Cloprostenolisopropylester;

(5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5-prostensäure;

(5Z)-(9S,11R, 15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5,13-prostadiensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäureisopropylester;

(5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäureamid;

PGF_2α-Isopropylester und

Fluprostenolisopropylester ausgewählt ist.

21. Prostaglandinprodukt nach Anspruch 20, wobei das Prostaglandin aus der Gruppe, bestehend aus (5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureisopropylester und Fluprostenolisopropylester ausgewählt ist.

22. Prostaglandinprodukt nach Anspruch 19, wobei die Zusammensetzung auf topische ophthalmische Verabreichung abgestimmt ist, und das oberflächenaktive Mittel ein polyethoxyliertes Rizinusöl umfaßt.

23. Prostaglandinprodukt nach Anspruch 22, wobei das polyethoxylierte Rizinusöl aus der Gruppe, bestehend aus PEG-2- bis PEG-200-Rizinusölen und hydrierten PEG-5- bis PEG-200-Rizinusölen ausgewählt ist.

24. Prostaglandinprodukt nach Anspruch 19, wobei der Polypropylenbehälter eine Polypropylenflasche ist, die auf topische Abgabe abgestimmt ist, und wobei das Polypropylen aus der Gruppe, bestehend aus isotaktischem Polypropylen, syndiotaktischem Polypropylen und Gemischen aus isotaktischem und syndiotaktischem Polypropylen ausgewählt ist.

25. Prostaglandinprodukt nach Anspruch 19, wobei die wässerige Prostaglandinzusammensetzung auf topische ophthalmische Verabreichung abgestimmt ist, und der Polypropylenbehälter eine Flasche mit einem kleinen Volumen ist, die auf topische ophthalmische Abgabe abgestimmt ist.

26. Prostaglandinprodukt nach Anspruch 25, wobei der Polypropylenbehälter eine ovale, syndiotaktische Polypropylenflasche ist.

27. Prostaglandinprodukt nach Anspruch 26, wobei die wässerige Prostaglandinzusammensetzung eine Mehrfachdosierungszusammensetzung ist, die ein ophthalmisch akzeptables Konservierungsmittel umfaßt.

Revendications

1. Utilisation d'un récipient de polypropylène pour accroître la stabilité d'une composition aqueuse de prostaglandine qui est conditionnée dans le récipient et qui comprend une prostaglandine et un agent tensioactif pharmaceutiquement acceptable.

2. Utilisation suivant la revendication 1, dans laquelle la composition aqueuse de prostaglandine comprend une prostaglandine choisie dans le groupe comprenant :

l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

le N,N-diméthylamide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclohexylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclopentylique d'acide (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester cyclopentylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,2-diméthylpropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester adamantylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-diisopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-dimétyhylphénylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyf-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-tri-hydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-méthoxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester tert-butylique d'acide (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15R)-3-oxa-17-phényl-9,11,15-trihydroxy-18,19,20-trinor-5-prosténoïque;

le (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-1-(diméthylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostène-11,15-diol;

le (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténol;

l'acide (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoïque;

le latanoprost (PhXA41 );

l'ester isopropylique de cloprosténol;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5-prosténoïque;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique de PGF₂α; et

l'ester isopropylique de fluprosténol.

3. Utilisation suivant la revendication 2, dans laquelle la prostaglandine est choisie dans le groupe comprenant l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque et l'ester isopropylique de fluprosténol.

4. Utilisation suivant la revendication 1, dans laquelle la composition est adaptée pour une administration ophtalmique topique et l'agent tensioactif comprend une huile de ricin polyéthoxylée.

5. Utilisation suivant la revendication 4, dans laquelle l'huile de ricin polyéthoxylée est choisie dans le groupe comprenant les huiles de ricin PEG-2 à PEG-200 et les huiles de ricin hydrogénées PEG-5 à PEG-200.

6. Utilisation suivant la revendication 1, dans laquelle le récipient de polypropylène est une bouteille de polypropylène adaptée pour une distribution topique et dans laquelle le polypropylène est choisi dans le groupe comprenant le polypropylène isotactique, le polypropylène syndiotactique et les mélanges de polypropylène isotactique et syndiotactique.

7. Utilisation suivant la revendication 1, dans laquelle la composition aqueuse de prostaglandine est adaptée pour une administration ophtalmique topique et le récipient de polypropylène est une bouteille de petit volume pour une distribution ophtalmique topique.

8. Utilisation suivant la revendication 7, dans laquelle le récipient de polypropylène est une bouteille de polypropylène syndiotactique, ovale.

9. Utilisation suivant la revendication 8, dans laquelle la composition aqueuse de prostaglandine est une composition à doses multiples comprenant un conservateur ophtalmiquement acceptable.

10. Procédé d'accroissement de la stabilité d'une composition aqueuse de prostaglandine comprenant une prostaglandine et un agent tensioactif pharmaceutiquement acceptable, dans lequel le procédé comprend :

le conditionnement de la composition aqueuse de prostaglandine dans un récipient de polypropylène.

11. Procédé suivant la revendication 10, dans lequel la composition aqueuse de prostaglandine comprend une prostaglandine choisie dans le groupe comprenant :

l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

le N,N-diméthylamide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclohexylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclopentylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester cyclopentylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,2-diméthylpropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester adamantylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-diisopropylique d'acide (5Z)-(9R,11R,15R)-9-chtoro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-dimétyhylphénylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyctohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'este isopropylique d'acide (5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-méthoxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester tert-butylique d'acide (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15R)-3-oxa-17-phényl-9,11,15-trihydroxy-18,19,20-trinor-5-prosténoïque;

le (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-1-(diméthylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostène-11,15-diol;

le (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténol;

l'acide (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoïque;

le latanoprost (PhXA41);

l'ester isopropylique de cloprosténol;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5-prosténoïque;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11 R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique de PGF₂α; et

l'ester isopropylique de fluprosténol.

12. Procédé suivant la revendication 11, dans lequel la prostaglandine est choisie dans le groupe comprenant l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque et l'ester isopropylique de fluprosténol.

13. Procédé suivant la revendication 10, dans lequel la composition est adaptée pour une administration ophtalmique topique et l'agent tensioactif comprend une huile de ricin polyéthoxylée.

14. Procédé suivant la revendication 13, dans lequel l'huile de ricin polyéthoxylée est choisie dans le groupe comprenant les huiles de ricin PEG-2 à PEG-200 et les huiles de ricin hydrogénées PEG-5 à PEG-200.

15. Procédé suivant la revendication 10, dans lequel le récipient de polypropylène est une bouteille de polypropylène adaptée pour une distribution topique et dans lequel le polypropylène est choisi dans le groupe comprenant le polypropylène isotactique, le polypropylène syndiotactique et les mélanges de polypropylène isotactique et syndiotactique.

16. Procédé suivant la revendication 10, dans lequel la composition aqueuse de prostaglandine est adaptée pour une administration ophtalmique topique et le récipient de polypropylène est une bouteille de petit volume pour une distribution ophtalmique topique.

17. Procédé suivant la revendication 16, dans lequel le récipient de polypropylène est une bouteille de polypropylène syndiotactique, ovale.

18. Procédé suivant la revendication 17, dans lequel la composition aqueuse de prostaglandine est une composition à doses multiples comprenant un conservateur ophtalmique ment acceptable.

19. Produit de prostaglandine comprenant :

(a) une composition aqueuse de prostaglandine comprenant une quantité thérapeutiquement efficace d'au moins une prostaglandine et un agent tensioactif pharmaceutiquement acceptable; et

(b) un récipient de polypropylène; dans lequel le composition aqueuse de prostaglandine est conditionnée dans le récipient de polypropylène.

20. Produit de prostaglandine suivant la revendication 19, dans lequel la prostaglandine est choisie dans le groupe comprenant :

l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11 R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

le N,N-diméthylamide d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclohexylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 1-méthylcyclopentylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester cyclopentylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,2-diméthylpropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester adamantylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-diisopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester 2,6-dimétyhylphénylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester t-butylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-méthoxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester tert-butylique d'acide (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester, isopropylique d'acide (5Z)-(9S,11R,15R)-3-oxa-17-phényl-9,11,15-trihydroxy-18,19,20-trinor-5-prosténoïque;

le (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(diméthylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostène-11,15-diol;

le (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténol;

l'acide (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoïque;

le latanoprost (PhXA41);

l'ester isopropylique de cloprosténol;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5-prosténoïque;

l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-S,11,15-trihydroxy-16-[(3-chlorophényl)oxy]-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'ester isopropylique d'acide (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque;

l'amide d'acide (5Z,13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque;

l'ester isopropylique de PGF₂α; et

l'ester isopropylique de fluprosténol.

21. Produit de prostaglandine suivant la revendication 20, dans lequel la prostaglandine est choisie dans le groupe comprenant l'ester isopropylique d'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque et l'ester isopropylique de fluprosténol.

22. Produit de prostaglandine suivant la revendication 19, dans lequel la composition est adaptée pour une administration ophtalmique topique et l'agent tensioactif comprend une huile de ricin polyéthoxylée.

23. Produit de prostaglandine suivant la revendication 22, dans lequel l'huile de ricin polyéthoxylée est choisie dans le groupe comprenant les huiles de ricin PEG-2 à PEG-200 et les huiles de ricin hydrogénées PEG-5 à PEG-200.

24. Produit de prostaglandine suivant la revendication 19, dans lequel le récipient de polypropylène est une bouteille de polypropylène adaptée pour une distribution topique et dans lequel le polypropylène est choisi dans le groupe comprenant le polypropylène isotactique, le polypropylène syndiotactique et les mélanges de polypropylène isotactique et syndiotactique.

25. Produit de prostaglandine suivant la revendication 19, dans lequel la composition aqueuse de prostaglandine est adaptée pour une administration ophtalmique topique et le récipient de polypropylène est une bouteille de petit volume pour une distribution ophtalmique topique.

26. Produit de prostaglandine suivant la revendication 25, dans lequel le récipient de polypropylène est une bouteille de polypropylène syndiotactique, ovale.

27. Produit de prostaglandine suivant la revendication 26, dans lequel la composition aqueuse de prostaglandine est une composition à doses multiples comprenant un conservateur ophtalmiquement acceptable.

Drawing